Childhood predictors of written expression in late adolescents with 22q11.2 deletion syndrome: a longitudinal study.

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is the second most prevalent genetic syndrome and has a characteristic academic and behavioural phenotype. The primary objective of the current study was to examine the childhood predictors of written expression achievement in adolescents with 22q11DS. Written expression is an important skill that can impact an individual's overall academic performance, potentially resulting in increased levels of stress and exacerbation of psychiatric symptoms. METHODS: A total of 119 participants were included in this study. Sixty-nine late adolescents with 22q11DS and 50 controls (consisting of a combined sample of 23 unaffected siblings of youth with 22q11DS and 27 community controls) participated in a 6-year longitudinal research project and received neuropsychological test batteries every 3 years. The Written Expression subtest of the Wechsler Individual Achievement Test - Second Edition was the primary outcome measure in the current project. RESULTS: Findings indicated differences in childhood predictors of adolescent written expression between participants in the 22q11DS group and participants in the control group. Whereas childhood verbal IQ scores predicted adolescent written expression for participants in the control group, childhood executive function and language skills were unique predictors of adolescent written expression in individuals with 22q11DS. CONCLUSIONS: Childhood predictors of late adolescent written expression in 22q11DS differ in meaningful ways from predictors in the non-22q11DS population. These results offer some guidance on the underlying factors that may be useful to consider when developing written expression interventions for children with 22q11DS.

No evidence for the presence of genetic variants predisposing to psychotic disorders on the non-deleted 22q11.2 allele of VCFS patients.

The velo-cardio-facial syndrome (VCFS) is caused by hemizygous deletions on chromosome 22q11.2. The VCFS phenotype is complex and characterized by frequent occurrence of neuropsychiatric symptoms with up to 25-30% of cases suffering from psychotic disorders compared with only ~1% in the general population (odds ratio≈20-25). This makes the 22q11.2 deletion one of the most prominent risk factors for schizophrenia. However, its penetrance for neuropsychiatric phenotypes is incomplete suggesting that additional risk factors are required for disease development. These additional risk factors could lie anywhere on the genome, but by reducing the normal diploid to a haploid state, the 22q11.2 deletion could result in the unmasking of otherwise recessive alleles or functional variants on the non-deleted 22q11.2 allele. To test this hypothesis, we captured and sequenced the whole 22q11.2 non-deleted region in 88 VCFS patients with (n=40) and without (n=48) psychotic disorders to identify genetic variation that could increase the risk for schizophrenia. Single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variants were called and their distributions were compared between the two diagnostic groups using variant-, gene- and region-based association tests. None of these tests resulted in statistical evidence for the existence of a genetic variation in the non-deleted allele that would increase schizophrenia risk in VCFS patients. Power analysis showed that our study was able to achieve >80% statistical power to detect association of a risk variant with an odd ratio of ⩾22. However, it is certainly under-powered to detect risk variant of smaller effect sizes. Our study did not provide evidence that genetic variants of very large effect size located on the non-deleted 22q1.2 allele in VCFS patients increase the risk for developing psychotic disorders. Variants with smaller effects may be located in the remaining 22q11.2 allele and elsewhere in the genome. Therefore, whole exome or even genome sequencing for larger sample size would appear to be the next logical steps in the search for the genetic modifiers of the 22q11.2-deletion neuropsychiatric phenotype.

Neurocognitive and familial moderators of psychiatric risk in velocardiofacial (22q11.2 deletion) syndrome: a longitudinal study.

BACKGROUND: Although risk for psychosis in velocardiofacial (22q11.2 deletion) syndrome (VCFS) is well established, the cognitive and familial factors that moderate that risk are poorly understood. METHOD: A total of 75 youth with VCFS were assessed at three time points, at 3-year intervals. Time 1 (T1) psychiatric risk was assessed with the Behavior Assessment System for Children (BASC). Data reduction of BASC scores yielded avoidance-anxiety and dysregulation factors. Time 2 (T2) neuropsychological and family function and time 3 (T3) prodromal/overt psychosis were assessed. Poisson regression models tested associations between T3 positive prodromal symptoms/overt psychosis and T1 psychiatric risk, T2 cognitive and familial factors, and their interactions. RESULTS: T1 avoidance-anxiety ratings predicted T3 prodromal/overt psychosis. T2 verbal learning scores moderated this association, such that individuals with low avoidance-anxiety scores and stronger verbal learning skills were the least likely to demonstrate prodromal/overt psychosis at T3. Low scores on a T2 visual vigilance task also predicted T3 prodromal/overt psychosis, independently of the effect of T1 avoidance-anxiety scores. T1 dysregulation scores did not predict T3 prodromal/overt psychosis in a linear manner. Instead, the association between dysregulation and prodromal/overt psychosis was amplified by T2 levels of family organization, such that individuals with low dysregulation scores and low family organization scores were the most likely to exhibit T3 prodromal/overt psychosis. CONCLUSIONS: Significant moderators of psychiatric risk in VCFS include verbal learning skills as well as levels of family organization, carrying implications for early identification and preventative treatment of youth with VCFS at highest risk for psychosis.

Predicting reading comprehension academic achievement in late adolescents with velo-cardio-facial (22q11.2 deletion) syndrome (VCFS): a longitudinal study.

BACKGROUND: The primary objective of the current study was to examine the childhood predictors of adolescent reading comprehension in velo-cardio-facial syndrome (VCFS). Although much research has focused on mathematics skills among individuals with VCFS, no studies have examined predictors of reading comprehension. METHODS: 69 late adolescents with VCFS, 23 siblings of youth with VCFS and 30 community controls participated in a longitudinal research project and had repeat neuropsychological test batteries and psychiatric evaluations every 3 years. The Wechsler Individual Achievement Test-2nd edition (WIAT-II) Reading Comprehension subtest served as our primary outcome variable. RESULTS: Consistent with previous research, children and adolescents with VCFS had mean reading comprehension scores on the WIAT-II, that were approximately two standard deviations below the mean and word reading scores approximately one standard deviation below the mean. A more novel finding is that relative to both control groups, individuals with VCFS demonstrated a longitudinal decline in reading comprehension abilities yet a slight increase in word reading abilities. In the combined control sample, WISC-III FSIQ, WIAT-II Word Reading, WISC-III Vocabulary and CVLT-C List A Trial 1 accounted for 75% of the variance in Time 3 WIAT-II Reading Comprehension scores. In the VCFS sample, WISC-III FSIQ, BASC-Teacher Aggression, CVLT-C Intrusions, Tower of London, Visual Span Backwards, WCST Non-perseverative Errors, WIAT-II Word Reading and WISC-III Freedom from Distractibility index accounted for 85% of the variance in Time 3 WIAT-II Reading Comprehension scores. A principal component analysis with promax rotation computed on the statistically significant Time 1 predictor variables in the VCFS sample resulted in three factors: Word reading decoding/Interference control, Self-Control/Self-Monitoring and Working Memory. CONCLUSIONS: Childhood predictors of late adolescent reading comprehension in VCFS differ in some meaningful ways from predictors in the non-VCFS population. These results offer some guidance for how best to consider intervention efforts to improve reading comprehension in the VCFS population.

Low cerebellar vermis volumes and impaired neuropsychologic performance in children treated for brain tumors and leukemia.

BACKGROUND AND PURPOSE: Injury of the cerebellar vermis may occur in children with brain malignancies. Because the vermis is involved in motor and cognitive functioning, the goal of this prospective longitudinal study was to evaluate treatment-related changes in vermal volumes and neuropsychologic performance in children receiving brain radiation of the cerebellum. MATERIALS AND METHODS: Ten patients (mean age, 11.6 years) and 10 healthy children (mean age, 12.1 years) were examined. Lobar vermal volumes and performance on neuropsychologic tests evaluating motor, visual, verbal, attention, memory, and executive functions were assessed at baseline and at 6-month follow-up visits. RESULTS: At baseline, lower mean vermal volumes and impaired performance on visual-spatial and fine-motor tasks were detected in patients. At 6-month follow-up, further decrease in vermal volumes was detected only in patients with medulloblastoma, who received the largest radiation doses to the entire vermis. The volume decrease was not associated with reduction in neuropsychologic performance compared with baseline. At 6-month follow-up, data from all subjects revealed an association between smaller vermal volumes and slower fine-motor speed and lower visual-spatial skills. CONCLUSIONS: Reduced brain-tissue volumes following radiation have been reported previously in pediatric patients. In this study, lower vermal volumes were detected even earlier, before radiation treatment was initiated or completed. Six months postradiation, vermal volume decreases detected in patients with medulloblastoma were not accompanied by declines in already poor neuropsychologic performance. In addition to radiation, the presence of brain malignancies and preradiation treatment may be important factors affecting cerebellar vermis tissue.

Temperament in velocardiofacial syndrome.

BACKGROUND: Velocardiofacial syndrome (VCFS) is a microdeletion syndrome caused by a 22q11.2 chromosomal deletion. METHODS: In this study, parents reported on their own temperament as well as the temperament of their child. Sixty-seven children with VCFS (mean age = 10.8, SD = 2.8; range 6-15), and age-, race- and gender-ratio matched samples of 47 community control participants (mean age = 10.4, SD = 2.6; range 6-15), and 18 sibling control participants (mean age = 12.1, SD = 1.9; range 9-15) took part in the current project. RESULTS: Children with VCFS have a temperament that may best be described as modestly difficult; while participants with VCFS were not more difficult across all temperamental domains, children with VCFS were rated by their parents as being: (1) less regular in their daily habits (e.g. eating at the same time each day, etc.); (2) less able to focus/sustain attention; (3) less cheerful/pleasant; (4) less likely to stay with an activity for a long time; and (5) less able to respond flexibly to changes in the environment. CONCLUSIONS: The best predictors of parent report of behavioural symptoms in children with VCFS were poor concordance between parent and child temperament across general activity level and mood domains.

Megalencephaly in NF1: predominantly white matter contribution and mitigation by ADHD.

BACKGROUND: Megalencephaly is a frequent CNS manifestation in neurofibromatosis type 1 (NF1); however, its tissue composition, modification by attention deficit hyperactivity disorder (ADHD), and relationship with unidentified bright objects (UBO) remain controversial. METHODS: Eighteen male patients with NF1, seven of whom had ADHD (NF1+ADHD), were compared with 18 age- and sex-matched controls in terms of MRI-, Talairach-based brain, cerebral, lobar, and sublobar gray and white matter volumes. Twelve subjects with NF1 had UBO in the centrencephalic region, whereas six had no UBO or exclusively infratentorial lesions. RESULTS: Patients with NF1 without ADHD (NF1-pure) had the largest total cerebral, gray, and white matter volumes with larger parietal/somatosensory white matter volumes than controls, particularly if UBO were present in the basal ganglia. All subjects with NF1 (including NF1+ADHD) had larger total and frontal white matter volumes than controls. Smaller frontal/right prefrontal gray matter volumes were found in NF1+ADHD when compared with NF1-pure patients. CONCLUSIONS: The increase in frontal and parietal white matter volumes in male patients with NF1, including the preferential centrencephalic distribution, supports the hypothesis that NF1's white matter pathology encompasses but is not limited to visible UBO. Male patients with NF1+ADHD, as compared with NF1-pure patients, showed frontal reductions that are largely consistent with those found in idiopathic ADHD.

Disproportionate increases of white matter in right frontal lobe in Tourette syndrome.

OBJECTIVE: Based on previous findings implicating abnormalities of cortico-striatal-thalamo-cortical circuitry in Tourette syndrome (TS), the authors performed a volumetric analysis of frontal and nonfrontal tissue (gray + white matter) in boys with TS, with and without attention deficit hyperactivity disorder (ADHD). METHODS: Frontal and nonfrontal gray and white matter compartment volumes, obtained by a MRI protocol, were analyzed with a 2 x 2 factorial multivariate analysis of variance approach for associations with a TS or ADHD factor in 11 boys with TS only, 14 with TS + ADHD, 12 with ADHD only, and 26 healthy boys. RESULTS: In subjects with TS, the right frontal lobe showed a larger proportion of white matter. In addition, results were consistent with previous reports of reduced frontal lobe volumes associated with ADHD. Our analyses suggested these reductions to be mainly the consequence of smaller gray matter volumes, particularly on the left. CONCLUSIONS: These findings, suggesting the volumetric composition of frontal lobe tissue to be different in TS, support the hypothesis proposing frontostriatal pathway involvement in the pathophysiology of the disorder. Differences in composition of right frontal lobe attributable to white matter do not definitively implicate the hypothesized fiber pathways; however, considered in the context of the unilateral directionality of frontal-striatal circuitry, these results suggest the white matter connections as one explanation for basal ganglia anomalies (loss of normal left > right asymmetry) in TS.

Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis.

BACKGROUND: Velocardiofacial syndrome, caused by a microdeletion on chromosome 22q.11, is associated with craniofacial anomalies, cardiac defects, learning disabilities, and psychiatric disorders. To understand how the 22q.11 deletion affects brain development, this study examined gray and white matter volumes in major lobar brain regions of children with velocardiofacial syndrome relative to control subjects. METHODS: Subjects were ten children with velocardiofacial syndrome and ten age- and gender-matched unaffected children. Coronal images were acquired with a 3-D spoiled gradient echo series and partitioned into 124, 1.5-mm contiguous slices. A stereotaxic grid was used to subdivide brain tissue into cerebral lobes, which were segmented into gray, white, and CSF compartments using an algorithm based on intensity values and tissue boundaries. Nonparametric statistics were used to compare lobar volumes of gray and white matter. RESULTS: Analyses indicated that children with velocardiofacial syndrome had significantly smaller volumes in nonfrontal, but not frontal, lobar brain regions. Volume reductions affected nonfrontal white matter to a greater extent than nonfrontal gray matter. CONCLUSIONS: The presence of white matter reductions may be related to disturbances in myelination or axonal integrity in velocardiofacial syndrome. Further work is required to delineate the nature and extent of white matter anomalies, and to link them to variation in the neurocognitive and neuropsychiatric phenotype of velocardiofacial syndrome.

Automated Talairach atlas-based parcellation and measurement of cerebral lobes in children.

This study applied a Talairach-based automated parcellation method, originally proposed for adults, to the measurement of lobar brain regions in pediatric study groups. Manual measures of lobar brain regions in a sample of 15 healthy boys, girls and adults were used initially to revise the original Talairach-based grid to increase its applicability to pediatric brains. The applicability of the revised Talairach grid was then tested on an independent sample of five girls with Rett syndrome. As Tables 3 and 4 in the text demonstrate, sensitivity, specificity and positive predictive values either remained unchanged or increased as a result of revising the sectors to fit the brains of children. High levels of sensitivity and specificity were achieved for all revised Talairach-based calculations in relation to the manual measures. Both positive predictive values and intraclass correlations between volumetric measures produced by the revised automated and manual methods varied with the relative size of the brain region. Values were relatively low for smaller structures such as the brainstem and subcortical region, and high for lobar regions. These results suggest that the automated Talairach atlas-based parcellation method can produce sensitive and specific volumetric measures of lobar brain regions in both normal children and children with brain disorders. Accordingly, the method holds much promise for facilitating quantitative pediatric neuroimaging research.

Neuroanatomical and neurocognitive differences in a pair of monozygous twins discordant for strictly defined autism.

In this study, we investigated the neuroanatomical similarities and differences between a pair of monozygotic, 7.5-year-old twin boys discordant for strictly defined autism, to identify neuroanatomical pathways that are impaired in individuals with autism. Although the unaffected twin did not fulfill the traditional diagnostic criteria for autism, he displayed constrictions in social interaction and play that were consistent with the broader phenotype for autism that has been described in nonautistic co-twins. Magnetic resonance imaging scans were obtained for each brother and compared with the scans of 5 age- and sex-matched unaffected peers. Quantitative analysis of brain anatomy revealed that the affected twin had markedly smaller caudate, amygdaloid, and hippocampal volumes, and smaller cerebellar vermis lobules VI and VII, in comparison with his brother. Both twins evidenced disproportionately reduced volumes of the superior temporal gyrus and the frontal lobe relative to the comparison sample. The results suggest the dysfunction of two separate but overlapping neuroanatomical pathways, ie, one subcortical network differentiating the twins from each other that may underlie the traditional neurobehavioral phenotype for strictly defined autism, and a second cortical network differentiating the twins from the comparison sample that may lead to the broader phenotype for autism.

Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome.

Evidence from numerous structural magnetic resonance imaging (MRI) studies has converged to implicate mesial temporal lobe structures in the pathophysiology of several developmental and psychiatric disorders. Efforts to integrate the results of these studies are challenged, however, by the lack of consistency, detail and precision in published protocols for the manual measurement of the amygdala and hippocampus. In this study, we describe a highly detailed, standardized protocol for measuring the amygdala and the hippocampus. Within the context of this protocol, we tested the inter- and intra-rater reliability of two frequently cited methods for normalizing the anatomical position of the amygdala and hippocampus prior to measurement. One method consisted of creating a coronal data set in which images are rotated in a plane perpendicular to the long axis of the hippocampus. The second method consisted of creating a coronal data set in which images are rotated in a plane perpendicular to the axis connecting the anterior and posterior commissures. Inter- and intra-rater reliability coefficients (using the intraclass correlation) ranged from 0.80 to 0.98, indicating that both methods for positional normalization are highly reliable. In addition, we tested the validity of each method by comparing the temporal lobe anatomy of children with fragile X syndrome to a group of unaffected children matched by age and gender. We found that hippocampal volumes in children with fragile X were significantly increased when either rotational method was used. These results replicated previous findings, suggesting that either method can be validly applied to neuronanatomic studies of pediatric populations.

Autistic behaviors among girls with fragile X syndrome.

Reports of autistic behaviors were examined for 30 school-age girls with fragile X (fraX) and 31 age- and IQ-matched controls through a structured interview administered to each girl's parent(s). IQ scores were obtained for each participant; anxiety, neuroanatomical, and molecular-genetic data were derived for girls with fraX. Girls with fraX had significantly more autistic behaviors than controls. These behaviors were qualitatively similar to those reported for boys with fraX, but were not correlated with IQ. Anxiety in girls with fraX was positively correlated with abnormal social and communication behaviors; posterior cerebellar vermis area was negatively correlated with measures of communication and stereotypic/restricted behaviors. Severity of stereotypic/restricted behaviors was negatively correlated with the prevalence of active non-fraX chromosomes. Thus anxiety and posterior cerebellar area measures had distinct associations with subsets of autistic behaviors; these associations may have important implications for understanding the neurobiology of autism.

Application of an automated parcellation method to the analysis of pediatric brain volumes.

New techniques in quantitative imaging are needed to accelerate understanding of brain development and function in children. In this study we evaluate the reliability and validity of an automated parcellation method for the measurement of large and small brain regions in normal and developmentally disabled children. We utilized an adaptation of the Talairach atlas to semi-automatically quantify brain volumes from 10 children with fragile X syndrome, 10 age- and gender-matched controls and 10 adult controls comparing them to 'gold standard' manually delineated regions. Excellent sensitivity, specificity, intra-class correlation and positive predictive value were achieved for large structures although results were less satisfactory for smaller structures, illustrating the limits of resolution of the method. Statistically significant differences in regional brain volumes were shown between males and females, children and adults, and individuals with fragile X and matched controls. This study demonstrates an automated method which rapidly and accurately quantifies large neuroanatomical structures, but not smaller structures. This method is sufficiently accurate to demonstrate some known anatomical differences in individuals with fragile X; the results suggest that this method could be applied to the assessment of brain volume in other neurodevelopmental disabilities.

Whose child is this? Assessment and treatment of children in foster care.

Clinicians who treat children in foster care must continually balance the development and therapeutic needs of the foster child with the expectations of a complex network of caretakers and professionals with whom the child interacts. A model that integrates individual and systemic issues in the assessment and treatment of children in foster care is proposed.

Saccades of hyperactive and normal boys during ocular pursuit.

Eye movements of hyperactive and normal boys were compared on a visual pursuit task in three experiments. In the first series of tests, irregular pursuit occurred more often in hyperactive than in normal boys. Hyperactive boys made more saccadic movements, their average saccades were larger, and they looked away from the pursuit path more frequently than the normal boys. In a second series of tests three years later, the differences between normal and hyperactive boys still existed. In a third set of experiments the effects of an attention task, different stimulus velocities and stimulant medication were studied in another group of control and hyperactive boys. With or without the attention task, hyperactive boys not receiving stimulant medication made more saccades than normal boys. Differences were greatest at lower target velocities and decreased at higher stimulus velocities. Differences between hyperactive and normal boys disappeared when the former received both stimulant medication and the attention task. The findings were the same in the two groups of hyperactive boys: they had more saccades superimposed on ocular pursuit than did normal boys. Differences between the groups may be related to their relative ability to attend to the target. The differences are of a magnitude that might make them useful as an adjunct for diagnosis of hyperactivity or for evaluating the effects of treatment.

Whom to refer for group psychotherapy.

The authors believe that group psychotherapy is a useful modality in terms of both economic use of resources and manpower and effective treatment for many common problems. Three major indications for group therapy are inappropriate patterns of interpersonal relationships, the tendency to act immediately on feelings, and the potential or existence of a transference that impedes individual therapy. Patients in these categories who are also in crisis or have a neurotic problem for which the development of a transference neurosis is indicated may require individual therapy instead of or in addition to group therapy. The attitude of the referring physician is crucial; he/she must provide support during the transition and must believe that group therapy can substantially benefit the patient.